Have you heard about Myhre syndrome? In this article, we explain in detail what Myhre syndrome is, a rare genetic disorder affecting one in every million people worldwide.

What is Myhre Syndrome?

Myhre syndrome is an extremely rare and little-known genetic condition characterized by a set of specific symptoms and physical and developmental features. It is a genetic disorder that affects multiple body systems. It is believed to be caused by mutations in the SMAD4 gene, which plays a crucial role in cellular signaling and tissue development.

It is estimated to have a prevalence of approximately one person per million worldwide. In fact, there are currently only about two hundred diagnosed cases globally. In Spain, the number of affected individuals is about 16.

Although it was first discovered and described in the 1980s, it is still under study today to better understand its cause, manifestations, and the best ways to manage and treat it.

Genetic and clinical studies are helping to unravel the underlying mechanisms of the condition and to develop better treatment and management strategies.

Causes of Myhre Syndrome

Myhre syndrome may be caused by mutations in the SMAD4 gene, which plays a fundamental role in cellular signaling and in regulating the growth and development of various tissues and organs in the body. Mutations in SMAD4 disrupt the normal function of the protein encoded by this gene, leading to the various clinical manifestations of the syndrome.

Details about the SMAD4 Gene

• Function of the SMAD4 Gene: the SMAD4 gene encodes a protein that is part of the TGF-beta (transforming growth factor beta) signaling pathway, which is important for the development and maintenance of connective tissue, cell growth regulation, and immune response.
• Mutation: the mutations causing Myhre syndrome are usually de novo, meaning they occur for the first time in the affected person and are not inherited from the parents. These mutations are typically point mutations in the gene that alter the function of the SMAD4 protein, leading to dysfunction in the cellular signaling pathways regulated by this protein.

Signs and symptoms of Myhre Syndrome

Documented cases have allowed for the identification of a consistent pattern of symptoms and characteristics.

Myhre syndrome presents a variety of signs and symptoms affecting many parts of the body, although not all individuals exhibit all possible features.

The most common include short stature, skeletal abnormalities, limited joint mobility, characteristic facial features, intellectual and behavioral problems, hearing loss, a tendency to accumulate scar tissue (fibrosis) in the skin and internal organs, and cardiac and pulmonary anomalies.

Below is a classification of them:

Facial and physical features

• Distinctive facial features: individuals with this syndrome often have a characteristic face with features such as a prominent forehead, flat nasal bridge, thin lips, and a small jaw (micrognathia).
• Short stature: most patients present with significantly shorter height than the average for their age and gender.
• Joint stiffness: stiffness in the joints is a common finding, which can lead to limitations in mobility and orthopedic problems. One of the most common difficulties is raising the arms or clenching the fists.
• Eye abnormalities such as strabismus.

Cognitive deficits

• Delay in motor and speech development: many children with Myhre syndrome experience delays in reaching developmental milestones such as sitting, walking, and speaking, which may be evident in the early years of life.
• Intellectual disabilities: most affected individuals present some degree of intellectual disability, which can range from mild to moderate or severe.
• Learning difficulties: children with this syndrome may face significant problems with learning in conventional educational settings and their performance in them. These difficulties may be related to issues with short-term memory, attention, abstract reasoning, information processing, and problem-solving.
• Language and communication problems: deficits in language development are common and can include both expressive language difficulties (difficulty articulating words or forming complex sentences) and receptive language difficulties (difficulty understanding what is said, following instructions, and participating in conversations).
• Behavioral problems: repetitive, stereotypical, or ritualistic behaviors may be common. Social interaction problems similar to those observed in autism spectrum disorders can also be seen.
• Mental health issues: some individuals may experience mental health issues such as anxiety or depression due to cognitive and social difficulties. In some cases, they may exhibit challenging or disruptive behaviors requiring behavioral intervention or psychological support.
• Motor difficulties: fine and gross motor skills may be affected, impacting the ability to perform daily tasks (such as writing or buttoning a shirt) and participate in physical activities. Coordination and balance may also be compromised.

Cardiac and respiratory problems

• Cardiovascular morphological anomalies: the vast majority of those affected may have congenital heart defects that require monitoring and, in some cases, medical intervention.
• Respiratory problems: stiffness in the tissues may affect lung and respiratory function, causing complications such as sleep apnea or restrictive pulmonary diseases.

Other health problems

• Hearing loss: hearing loss, often due to recurrent otitis media, is a relatively common feature.
• Gastrointestinal problems: some patients experience digestive issues, including gastroesophageal reflux and constipation.

Diagnosis and treatment 

The diagnosis of Myhre syndrome is based on clinical evaluation and can be confirmed through genetic tests identifying mutations in the SMAD4 gene.

Most cases are diagnosed in infancy or early childhood due to developmental delays and evident physical characteristics.

Given the complex and multisystem nature of the syndrome, and the fact that there is still no cure, treatment is focused on managing symptoms through a multidisciplinary approach.

Multidisciplinary management

• Regular medical care: regular monitoring by a team of specialists including geneticists, cardiologists, orthopedists, and speech therapists, among others.
• Therapeutic interventions: physical and occupational therapies can help improve mobility and functionality.
• Educational support: special education programs and classroom support may be necessary to address learning difficulties.

Psychosocial support

Psychosocial support for families is also crucial. Support groups and organizations dedicated to rare diseases can provide valuable resources and an emotional support network for parents and caregivers.

Conclusion

Myhre syndrome, although rare, is a condition that presents significant challenges for those affected and their families. With proper understanding and interdisciplinary management, it is possible to improve the quality of life for these patients. Ongoing awareness and research are essential for advancing knowledge and treatment of this complex condition. 

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